Probably the single factor most dramatically increasing a woman's risk of breast cancer is the presence of the disease in her immediate family, especially if more than one relative has had breast cancer, or if the relative was affected bilaterally or at a young age. However, we do not know if this increased risk is due to social, dietary, or environmental factors which predispose the family to breast cancer or to inherited factors which increase susceptibility to the disease. The objective of this project is to unravel the genetic and environmental contributions to breast cancer susceptibility in families with high incidence of the disease. Within such families, epidemiologic tools will be used to compare affected women with their unaffected relatives, while segregation and linkage analysis will be used to test specific genetic and environmental models for breast cancer susceptibility. We will investigate both individual, very large families with high incidence of breast cancer and four series of smaller families, each identified through one cancer patient from a population-based cancer registry. The goal is to elucidate a genetic model for inheritance of susceptibility to breast cancer, estimate the proportion of breast cancer among American women influenced by genetic susceptibility, and determine environmental or cultural factors which influence the expression of genetic susceptibility. These results are of immediate value for young women in high-risk families and are more generally applicable to the study of breast cancer etiology, in that hormonal, immunological, and other biological profiles of genetically susceptible, as-yet-unaffected young women provide a model for development of breast cancer in the general population.